Nonocular Findings Research Articles

A naturally occurring canine model of syndromic congenital microphthalmia.

In humans, the prevalence of congenital microphthalmia is estimated to be 0.2-3.0 for every 10,000 individuals, with nonocular involvement reported in ∼80% of cases. Inherited eye diseases have been widely and descriptively characterized in dogs, and canine models of ocular diseases have played an essential role in unraveling the pathophysiology and development of new therapies. A naturally occurring canine model of a syndromic disorder characterized by microphthalmia was discovered in the Portuguese water dog. As nonocular findings included tooth enamel malformations, stunted growth, anemia, and thrombocytopenia, we hence termed this disorder Canine Congenital Microphthalmos with Hematopoietic Defects. Genome-wide association study and homozygosity mapping detected a 2 Mb candidate region on canine chromosome 4. Whole-genome sequencing and mapping against the Canfam4 reference revealed a Short interspersed element insertion in exon 2 of the DNAJC1 gene (g.74,274,883ins[T70]TGCTGCTTGGATT). Subsequent real-time PCR-based mass genotyping of a larger Portuguese water dog population found that the homozygous mutant genotype was perfectly associated with the Canine Congenital Microphthalmos with Hematopoietic Defects phenotype. Biallelic variants in DNAJC21 are mostly found to be associated with bone marrow failure syndrome type 3, with a phenotype that has a certain degree of overlap with Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and reports of individuals showing thrombocytopenia, microdontia, and microphthalmia. We, therefore, propose Canine Congenital Microphthalmos with Hematopoietic Defects as a naturally occurring model for DNAJC21-associated syndromes.

Prevalence and Causes of Subconjunctival Hemorrhage in Children.

Subconjunctival hemorrhage (SCH) is a reported sign of occult abusive injury, but there are limited published data about SCH during childhood. We sought to determine the prevalence and causes of SCH in children. This is a retrospective cross-sectional study of children seen by pediatric ophthalmologists in an outpatient setting over 4 years. Primary outcomes were prevalence and causes of SCH, based on history, physical ocular and nonocular findings, and laboratory and imaging studies. Subconjunctival hemorrhage prevalence was determined including and excluding eye surgery to reduce bias in the prevalence estimate. We studied 33,990 children, who underwent 86,277 examinations (median age, 5 years; range, 2 days to 18 years; 9282 younger than 2 years, 13,447 age 2-7 years, 11,261 age 8-18 years). There were 949 cases of SCH (1.1%; 95% confidence interval, 1.0-1.2). When surgery was excluded, there were 313 cases (prevalence, 0.4%; 95% confidence interval, 0.3-0.4), of which 261 (83%) were due to trauma; 40 (13%) ocular surface inflammation, including infectious conjunctivitis; 7 (2%) orbital or conjunctival lesion; 3 (1%) vessel rupture from choking or cough; and 2 (1%) coagulopathy related. Across all ages, including less than 2 years, trauma and inflammation together accounted for 94% to 97% of all cases of SCH. Subconjunctival hemorrhage is uncommon in children. The great majority of cases are due to trauma. All children with SCH, including infants and young children, should be closely examined to identify other ocular or nonocular signs of trauma.

Evidence-Based Screening to Optimize the Yield of Positive Ophthalmologic Examinations in Children Evaluated for Suspected Child Abuse.

To determine nonocular findings associated with significant retinal hemorrhage on dilated fundus examination in cases of suspected child abuse. This was a retrospective chart review from May 2014 to August 2021 at a level-1 trauma center. Two hundred seventy-four patients met the following inclusion criteria: (1) children 36 months and younger; (2) concern for child abuse; and (3) had an ophthalmology consultation. Through univariate and multivariate logistic regression, the study produced a screening algorithm for ophthalmic work-up in child abuse. One or more abnormal neuroimaging findings had a statistically significant association with retinal hemorrhages and produced the strongest association with a univariate odds ratio of 170 (confidence interval: 10.245 to > 999.999). The multivariate model (P < .0001 with a c-statistic of 0.980) proposes using the following variables for predicting retinal hemorrhage on examination: abnormal neuroimaging, Glasgow Coma Scale score less than 15, altered mental status on examination, seizure activity, vomiting, bruising, scalp hematoma/swelling, and skull fractures. This study elucidates clinical and imaging factors that correlate to retinal findings, validating previously studied variables and introducing new variables to be considered. The authors propose an evidence-based screening algorithm to increase the yield of positive dilated examinations and decrease the burden of potentially unnecessary child abuse ophthalmologic examinations. [J Pediatr Ophthalmol Strabismus. 2022;59(5):310-319.].

Novel PAX6 variant in a family with ophthalmologic, pancreatic, and olfactory features.

Variants in the PAX6 gene have been associated with ophthalmologic, neurologic, and pancreatic differences. We report on a proband, mother, and affected brother who presented with congenital cataracts and glaucoma at a young age. Nonocular findings are also reported among these family members. After a congenital cataracts next-generation sequencing (NGS) gene panel was found to be nondiagnostic in 2016, a more expanded panel in 2020 revealed a novel variant: c.178T > A; p.Tyr60Asn in exon 6 of the PAX6 gene in the proband. The variant is also present in the affected mother and affected brother; it is absent in an unaffected brother. The clinical findings of these three relatives, in conjunction with their genetic testing and the associated PAX6 features reported in the literature, suggest that this novel familial variant may be an underlying etiology for these individuals’ ophthalmologic, pancreatic, and olfactory symptoms.

Patterns of retinal hemorrhage associated with cardiac arrest and cardiopulmonary resuscitation

Hypoxia and cardiopulmonary resuscitation (CPR) have been proposed as causes of retinal hemorrhage (RH) in children evaluated for abusive head trauma (AHT). We sought to determine the prevalence and characteristics of RH in children who underwent CPR after cardiac arrest. This was a prospective, single-center, consecutive observational study of 38 children (<18 years of age). Indirect ophthalmoscopic examination was completed by an ophthalmologist within 48 hours of CPR. Extensive medical records data were collected to assess for potential confounding factors. Outcomes included the presence and pattern of RH. Of the 38 children, 20 had in-hospital arrest; 18 had out-of-hospital arrest. The median duration of CPR was 10 minutes. Seven children had RH, of whom 6 had an RH pattern consistent with coexistent medical conditions: 4 AHT diagnosable with nonocular findings, including subdural and subarachnoid hemorrhage, rib fractures, abdominal injury (RH pattern: diffuse, numerous, intraretinal and/or multilayered RH); 1 septic shock (RH pattern: 1-2 posterior pole RH); 1 ruptured arteriovenous malformation (RH pattern: 4-8 peripapillary RH). The seventh child had unwitnessed cardiac arrest due to nonfatal drowning and a single superficial intraretinal peripapillary hemorrhage. CPR for cardiac arrest is rarely associated with RH, which, absent coexisting conditions causing retinal hemorrhage, are intraretinal, few in number, and located in the posterior pole. In children who have undergone CPR, when RH are multilayered, or are more than a few in number, or extend outside the posterior pole, another etiology for the RH should be sought.

Children and young adults with anophthalmia and microphthalmia: Diagnosis and Management.

Congenital anophthalmia (A) and microphthalmia (M) are rare developmental defects, which could be isolated or syndromic. Our objective was to describe a cohort of children and young adults with A/M treated with ocular prosthesis, emphasizing clinical features, diagnosis, treatment, and follow-up. Eighteen individuals (10 female) with unilateral A (n=3) and M (n=15) with a mean age of 9.5years (range 0.8-31.8) and treated with ocular prosthesis were included. Data on medical history, clinical examinations and management of ocular prosthesis were collected. Genetic screening with microarray and whole-exome sequencing targeting 121 A/M-related genes was performed. A/M appeared isolated (seven cases) or as part of a syndromic condition (11 cases). In 4/16 patients, mutations were detected in TFAP2A, CHD7, FOXE3 and BCOR-genes. In one patient, a possibly causal microdeletion 10q11 was shown. Associated ocular anomalies such as cataract and cysts were found in 16 (89%) of the A/M eyes, and in nine (50%) ophthalmological findings were found in the fellow eyes. The median ages at which the conformer and ocular prosthesis first were initiated were 7.8months and 1.5years. 16/17 patients fulfilled satisfactory orbital growth and cosmetic results when treated with ocular prosthesis from an early age. Based upon our findings, a multidisciplinary approach, including genetic assessment, is necessary to cover all aspects of A/M. Imaging, ultrasound and visual evoked potentials should be included. Early management is crucial for the outcome, in terms of non-ocular findings, vision in the fellow eye, and for facial cosmetic development.

Retinal Findings in Young Children With Increased Intracranial Pressure From Nontraumatic Causes.

Increased intracranial pressure (ICP) has been suggested in legal settings as an alternative cause of retinal hemorrhages (RHs) in young children who may have sustained abusive head trauma. We assessed the prevalence and characteristics of RHs in children with increased ICP. We conducted a prospective, multicenter study of children <4 years old with newly diagnosed increased ICP as determined by using direct measurement and/or clinical criteria. Infants who were premature, neonates, and suspected survivors of abusive head trauma were excluded on the basis of nonocular findings. Fundus examinations were performed; extent, number, and type of RH in each of 4 distinct retinal zones were recorded. Fifty-six children (27 boys) were studied (mean age 15.4 months; range 1-43 months). All of the children had elevated ICP that required intervention. One child had papilledema. No child (0%; 95% confidence interval: 0%-6.4%) or eye (0%; 95% confidence interval: 0%-3.3%) was found to have an RH. Causes of increased ICP included hydrocephalus, intraventricular hemorrhage, congenital malformations, malfunctioning shunts, and the presence of intracranial space-occupying lesions. Although acute increased ICP can present in children with a pattern of peripapillary superficial RHs in the presence of papilledema, our study supports the conclusion that RHs rarely occur in the absence of optic disc swelling and do not present beyond the peripapillary area in the entities we have studied.

Evaluation of Temporal Association Between Vaccinations and Retinal Hemorrhage in Children.

Vaccinations have been proposed as a cause of retinal hemorrhage in children, primarily as part of a defense strategy in high-stakes abusive head trauma cases. If vaccination injections cause retinal hemorrhage, this consideration would affect the evaluation of children for suspected child abuse. To describe the prevalence and causes of retinal hemorrhage among infants and young children in an outpatient ophthalmology clinic and to test the hypothesis that, if vaccination injections cause retinal hemorrhage, then retinal hemorrhage would be seen frequently and be temporally associated with immunization. Retrospective cohort study between June 1, 2009, and August 30, 2012, at The Children's Hospital of Philadelphia pediatric ophthalmology clinics among 5177 children 1 to 23 months old undergoing a dilated fundus examination as an outpatient for any reason. Children with intraocular surgery or active retinal neovascularization were excluded from the study. The prevalence and causes of retinal hemorrhage, as well as the temporal association between vaccination injection within 7, 14, or 21 days preceding examination and retinal hemorrhage. Among 7675 outpatient fundus examinations, 9 of 5177 children had retinal hemorrhage for a prevalence of 0.17% (95% CI, 0.09%-0.33%). All 9 had abusive head trauma diagnosable with nonocular findings. Among a subset of 2210 children who had complete immunization records and underwent 3425 fundoscopic examinations, 163 children had an eye examination within 7 days of vaccination, 323 within 14 days, and 494 within 21 days. No children had retinal hemorrhage within 7 days of vaccination, 1 child had hemorrhage within 14 days, and no additional child had hemorrhage within 21 days. There was no temporal association between vaccination injection and retinal hemorrhage in the prior 7 days (P > .99), 14 days (P = .33), or 21 days (P = .46). Retinal hemorrhage was rare among outpatients younger than 2 years. Considering both immediate and delayed effects, no temporal association existed between vaccination injection and retinal hemorrhage. Vaccination injections should not be considered a potential cause of retinal hemorrhage in children, and this unsupported theory should not be accepted clinically or in legal proceedings. Ophthalmologists noting incidental retinal hemorrhage on an outpatient examination should consider a child abuse evaluation in the absence of other known ocular or medical disease.

CHN1 mutations are not a common cause of sporadic Duane's retraction syndrome

<i>CHN1</i> mutations are not a common cause of sporadic Duane's retraction syndrome

Asymptomatic Renal Cell Carcinoma as a Finding of Bardet Biedl Syndrome

Retinitis pigmentosa represents a class of disorders that exhibit dystrophy of the photoreceptors, pigment epithelium, and often systemic abnormalities, Bardet-Biedl syndrome is a form of retinitis pigmentosa that has characteristic non-ocular findings including polydactyly, obesity, learning difficulties, male hypogonadism, and renal anomalies. Though none of these renal anomalies are neoplastic, there is a 17 fold increased risk for renal cell carcinoma in obligate carriers of Bardet-Biedl syndrome. Herein, we describe a case of metastatic renal cell carcinoma discovered in a patient with Bardet-Biedl syndrome.

Genotype-Phenotype Correlations in Axenfeld-Rieger Malformation and Glaucoma Patients withFOXC1andPITX2Mutations

To improve the understanding of Axenfeld-Rieger Malformation (ARM)-associated glaucoma and to determine the best glaucoma treatment for patients with ARM who have known genetic defects in FOXC1 or PITX2. Clinical data were collected from patients with diagnosed ARM, in whom we had previously identified disease-causing mutations in either the FOXC1 or PITX2 genes, by examination of patient records and use of clinical questionnaires. One hundred twenty-six patients with ARM, representing 20 different probands, with FOXC1 and PITX2 alterations were included in the study. ARM-associated glaucoma is a bilateral anterior segment dysgenesis disease that affects males and females equally. Seventy-five percent of the patients with ARM who participated in this study had glaucoma that had developed in adolescence or early adulthood. Of note, the patients with nonocular findings were more likely to have PITX2 defects than FOXC1 defects. Glaucoma in only 18% of patients with either PITX2 or FOXC1 genetic defects responded to medical or surgical treatment (used solely or in combination). Patients with FOXC1 mutations have the mildest prognosis for glaucoma development, whereas patients with PITX2 defects and patients with FOXC1 duplication have a more severe prognosis for glaucoma development than do patients with FOXC1 mutations. In the present study, current medical therapies do not successfully lower intraocular pressure or prevent progression of glaucoma in patients with ARM who have FOXC1 or PITX2 alterations. This clinical study also provides useful diagnostic criteria to identify the gene responsible for ARM.

Ocular and nonocular findings in patients with aniridia

Background: Aniridia typically appears as a familial condition with autosomal dominant inheritance but can present as an isolated disease or sporadically in association with several syndromes. In this report we describe the various ocular manifestations of aniridia as well as the association of familial aniridia with two different ocular and systemic abnormalities present across three generations in two different families.Methods: Descriptive case series of 33 patients (66 eyes) with aniridia.A full eye examination was performed at the beginning of the study, including past medical history, family history and type of inheritance, assessment for fixation pattern and presence of nystagmus, visual acuity testing, refraction, slit-lamp examination, gonioscopy, fundus examination with pupil dilation and anterior segment photography; additional glaucoma testing was done if the patient had high intraocular pressure. Patients were followed for at least 2 years. The interval between follow-up visits, which included gonioscopy and fundus examination with pupil dilation, depended on the findings in each case.A urology consultation was requested in all sporadic aniridia cases; consultations in psychiatry and gynecology were requested on the basis of the medical history or clinical suspicion during the ophthalmologic examination.Results: Ten patients (30%) had sporadic aniridia, with no previous family history; Wilms' tumour did not develop in any of them during the follow-up period. In the autosomal dominant group, ocular and systemic findings present in combination with aniridia were observed in 20 patients in the two families. Family I had aniridia and developmental delay or behavioural disorders in three generations as well as high myopia (greater than 6.00 dioptres) in all affected adults. Family 2 presented a wide phenotypic variability of aniridia with myopia in three generations. Open-angle glaucoma developed in three young adults in this family, and two members were found to have gynecologic abnormalities (hypoplastic uterus and imperforate vagina). Myopia was the most prevalent refractive error (64%) in the 33 patients. Refractive correction significantly improved the visual acuity in half of these cases. Glaucoma was present in 10 patients (30%) and was the main cause of vision loss, provoking blindness in two cases (6%). Affected patients manifested progressive angle closure or presented with open-angle glaucoma.Interpretation: Ophthalmologists should consider aniridia in patients with unusual iris malformations. Examination of family members may be key in making the diagnosis.Any refractive error should be corrected, as this may improve vision.All aniridic patients should be screened regularly for glaucoma, as this condition may occur at any age and can lead to permanent vision loss. Systemic and ocular associations should be considered as they may present in combination with anirida. In our series, developmental delay or behavioural disorders and myopia were associated conditions.

The spectrum of postmortem ocular findings in victims of shaken baby syndrome

Background: Ophthalmologists and ocular pathologists are called on to help identify children who have undergone violent shaking. The objective of this study was to describe the spectrum of postmortem ocular findings in victims of shaken baby syndrome and to correlate the ocular findings with the nonocular features found at autopsy.Methods: The ocular pathology registry at the University of Ottawa Eye Institute was reviewed to identify all victims of fatal shaken baby syndrome whose eyes had been submitted for examination between Apr. 1, 1971, and Dec. 31, 1995. Autopsy reports were accessed from the hospital charts of the identified patients.Results: Six patients, aged I to 34 months, were identified. Intraocular findings ranged from a focal globular hemorrhage at the posterior pole to extensive intraocular hemorrhage involving the entire retina with perimacular folds. All the children had evidence of optic nerve sheath hemorrhage. Nonocular findings included intracranial hemorrhage (in all cases), skull fracture (in two), rib fractures (in three) and high spinal cord hemorrhage (in four). The extent of the intraocular hemorrhage was not consistent with the nonocular findings.Interprétation: Abused children may display a range of postmortem ocular findings, with intraocular hemorrhage varying from minimal to severe. These findings may not correlate with the severity of the child's other injuries. The presence of any retinal or optic nerve sheath hemorrhage in an infant, in the absence of an appropriate explanation for these findings, should raise suspicion of child abuse.

Kongenitale Amaurose Leber: Diagnose, Verlauf und Differentialdiagnose

Leber's congenital amaurosis (LCA) had been diagnosed on/in 42 children between 1968 and 1996 at the Deptm. of Ophthalmology, University Hospital Zurich. We reexamined critically this rare diagnosis in retrospect and with new examinations where possible. Clinical and electroretinographic (ERG) results, often obtained in general anesthesia, were re-evaluated and when possible repeated in new examinations. Thirty-three of the total 42 patients presented with an extinguished, 35 with markedly reduced, and 6 with minimal ERGs. A profound visual loss (from no light perception to 20/200), nystagmus and strabismus were the principal symptoms. The heterogeneity of retinal findings ranged from normal to salt and pepper or bone spicules pigmentation and pronounced chorioretinal atrophy. Vascular attenuation and rarification were frequent. Patients with nonocular findings such as mental retardation (n = 12), renal (n = 3) and skeletal (n = 4) abnormalities revealed no differing ERG- or retinal findings. The oculodigital sign (eye-poking) was found in 25%, and parental consanguinity was evident in 10% of the cases. In 16 patients that were reexamined, the progression of the disease was characterized by an increase in retinal pigmentary changes, attenuation of retinal vessel, and further diminuation of the visual acuity (n = 6). Upon review, the diagnosis had to be revised in 8 patients as juvenile retinitis pigmentosa and in one as infantile Refsum syndrome. Bilateral visual impairement in infants should be assessed clinically and electroretinographically within the first year. Neuropediatric and metabolic examinations meaningfully complement the diagnostic procedures.

Ocular Syndromes and Systemic Diseases

Every compulsive ophthalmologist (and certainly every ophthalmology resident) has wished for a single reference source so complete that it may be consulted with no fear of omitting a condition from the differential diagnosis or of overlooking a significant finding when the diagnosis is known. I suspect that such fear is the motivating force behind Ocular Syndromes and Systemic Diseases . The book is divided into two sections. The first and main section lists syndromes and systemic diseases that may have ocular involvement. Under each heading, a general description of the entity, ocular findings, and nonocular findings are found. A few references are provided for each entity. The second section lists ocular signs and symptoms; under each heading, the conditions in which the symptoms or finding may occur are grouped. The primary limitations of the first section are the brevity and resultant lack of depth of each description; only a thumbnail sketch